The candidate, Dr. Edward Botchwey, is experienced in orthopaedic biomaterials and tissue engineering. His long term career goal is to establish an independent research laboratory to pursue his interests in the development of experimental and computational methods to study the role of angiogenesis and microvascular remodeling in bone tissue engineering. His intermediate term objective is to work together with mentor Dr. Thomas Skalak, chair of biomedical engineering at the University of Virginia, to leverage the tremendous resources available at UVA to achieve this goal. This proposal outlines a career development plan to design and build new enabling technologies capable of co-cultivating osteoblastic cells and vascular endothelial cells within tissue engineered scaffolds, and varying the geometric arrangement of cells so that optimization of both bone remodeling and neo-vascularization can be explored. In vivo experimental assessment and novel computational modeling approaches will be developed to identify the geometries of combined cell distribution that are most conducive to bone healing and vascular remodeling. The specific objectives of the proposal are 1) to quantify the effects of perfusion flow velocity and internal pore network geometry on rMSC proliferation, gene expression, and mineralized deposition within 3-D microsphere based scaffolds in a customized perfusion. 2) to develop new experimental methods to co-culture rat microvascular endothelial cells (rVECs) within mineralized rMSC constructs formed in Aim1. Specifically, rVECs will be cultivated according to two predetermined geometric configurations, (a) uniformly dispersed network within the scaffolds, and (b) externally laminated layer around the scaffolds. 3) to combine experimental and computational methods to determine whether the geometric distribution of vascular endothelial cells within mineralized bone tissue engineered scaffolds developed in Aim 2 enhance microvascular network remodeling and ectopic bone formation in a customized rat window chamber model in vivo.